Apparatus for removing components from solutions

ABSTRACT

A dispensing device having a container body defining a solution retaining chamber therein, the container having an outlet for dispensing the solution from the chamber and means for removing a component from the solution as the solution is dispensed from the chamber through the container outlet. A method is provided for administering to a patient a pharmacologically active substance which substance is stable only at a pH value which is extreme in the acidic or alkaline region and at which pH value the substance cannot be administered without causing discomfort and/or injury to the patient. The substance is maintained in a solution or dispersion at the pH at which it is stable until the time of administration. At this time the substance is administered through a chamber containing an ion exchange resin which changes the pH of the solution or dispersion to a value which will not cause discomfort and/or injury to the patient.

This is a divisional application of Ser. No. 08/024,224, filed Mar. 1,1993 (now U.S. Pat. No. 5,496,471), which is a continuation-in-part ofnow abandoned application Ser. No. 07/873,215, filed Apr. 24, 1992,which is a continuation-in-part of now abandoned application Ser. No.814,728, filed Dec. 19, 1991, which application is a division ofapplication Ser. No. 671,967, filed Mar. 18, 1991 (now U.S. Pat. No.5,080,800), which is a division of application Ser. No. 461,988, filedJan. 8, 1990 (now U.S. Pat. No. 5,056,689).

BACKGROUND OF THE INVENTION

The present invention relates to a solution dispenser and moreparticularly to a dispenser in which preservatives and other componentsmay be removed from a solution as the solution is dispensed. Theinvention also provides a method for the removal of preservatives andother components from a solution as the solution is dispensed. In oneembodiment, the invention provides a dispenser and method for alteringthe pH of a solution or dispersion as it passes through a dispenser.

Many solutions are available for making contact lenses more comfortable,safer, and easier to wear. For example, wetting solutions facilitate thewetting of a lens, soaking solutions serve as anti-microbial storagemedium and prevent dehydration and distortion of the lens, and cleaningsolutions remove accumulated eye secretions and other contaminants fromlenses. A large number of other solutions are also used by contact lenspatients. These ophthalmic solutions are typically marketed insqueezable plastic containers or aerosol cans having a nozzle throughwhich the solution is dispensed.

Because these solutions come in contact either directly or indirectlywith the eye, it is very important that they be free of microbialgrowth. To this end, it is common practice for preservatives to beprovided in these solutions. Among the preservatives used in ophthalmicsolutions are polymoxin B sulfate, quaternary ammonium compounds,chlorobutanol, organic mercurials, p-hydroxybenzoic acid esters, andcertain phenyls and substituted alcohols.

A problem exists, however, in that the preservatives used in theophthalmic solutions can cause eye irritation if used in highconcentrations. For example, benzalkonium chloride (BAK) is used as apreservative in ophthalmic solutions and has broad anti-bacterial andanti-fungal activity when used with other components, such as disodiumethylene diaminetetraacetic acid (EDTA). However, it has been reportedthat repeated use of BAK can denature the corneal protein and causeirreversible eye damage. Also, in addition to chemical sensitivity, anumber of contact lens wearers have allergic reactions to thepreservatives used in ophthalmic solutions, even at relatively lowconcentrations.

The typical remedy for overcoming chemical sensitivity and allergicreactions to preservatives in ophthalmic solutions entails switching thepatients to an unpreserved solution. However, unpreserved solutionspresent problems in marketing, as well as in home storage, in that oncethe container housing the solution is opened, the solution quicklybecomes contaminated and unsuitable for further use. They also tend tobe very expensive to produce.

Therefore, there exists a need for an apparatus which removespreservatives, as well as other components, from a solution as thesolution is dispensed to a patient.

There exists a further need for such an apparatus which is easilymanufactured and economical to use.

There exists a further need for an apparatus which may be attached to astandard solution container.

SUMMARY OF THE INVENTION

The present invention relates to a device for removing a component,including but not limited to preservatives, from ophthalmic and othersolutions as the solution is dispensed from a container. As employedherein the term "solution" is employed in a broad sense to includedispersions of one or more of the active components in a liquid to bedispensed from the container. The device preferably comprises acontainer having squeezable sidewalls defining a solution retainingchamber, but may also be an aerosol can or other container. Thecontainer also preferably includes a neck portion and a dispensing headhaving a container outlet on its end through which the solution isdispensed. Means for removing the component from the solution as thesolution is dispensed from the chamber through the container outlet arealso provided.

In a first embodiment, the means for removing a component from thesolution comprises a scavenging material provided within the path of thesolution as the solution is dispensed. In this embodiment, the device isa standard solution container housing a solution having the component tobe removed, and the scavenging material is held within the dispensinghead. The scavenging material may have a positive charge for scavengingnegatively charged components or it may have a negative charge forscavenging positively charged components or it may be a material whichselectively scavenges components by a size exclusion mechanism or it maycomprise any other means for removing a component from solution.

In an alternative embodiment, a fitment may be utilized having a fitmentbody which is releasably engageable with a standard solution container.The fitment includes passage means within its body for allowing passingof the solution from the container to a fitment outlet. In thisembodiment, the means for removing a component may comprise a scavengingmaterial provided within the fitment so as to be within the path of thesolution as the solution is dispensed from the container outlet to thefitment outlet. The fitment has the advantage of being able to beadapted to standard solution containers.

Also, means for providing a control of the flow of solution out of thecontainer may be provided. For example, a check valve may be providedwithin the final dispensing outlet to prevent backflow of solution intothe container following use. Additionally, means for regulating the flowof air into the container, namely, a second check valve, may be placedwithin the neck portion of a squeezable container for allowing air toflow into a depressed container, thereby restoring the container to itsoriginal shape. This embodiment will minimize the incidence of microbialgrowth in the area of the dispensing head proximate the final dispensingoutlet.

Another embodiment of the present invention provides a dispensing devicewhich is capable of holding an ophthalmic solution at a first pH anddispensing the solution at a different pH. The term "ophthalmicsolution" as used herein is intended to mean any solution used in oraround the eye, such as a pharmaceutical, eye wash, contact lenssolution, or otherwise. The device includes a container body defining asolution retaining chamber therein for retaining the solution having thepredetermined first pH and an outlet for dispensing the solution fromthe chamber; as well as means for changing the pH of the solution as thesolution is dispensed from the chamber through the container outlet.Preferably, the pH changing means are in the form of an ionic exchangematerial provided within the path of the solution as the solutiontravels from the chamber to the container outlet. For example, the pHchanging means may be an anionic exchange material for removingpositively charged ions from the solution to raise the pH of thesolution as the solution is dispensed from the chamber through thecontainer outlet, or may be a cationic exchange material for removingnegatively charged ions from the solution to lower the pH of thesolution as the solution is dispensed from the chamber through thecontainer outlet. As with the other embodiments of the presentinvention, the pH changing means may be an integral part of thecontainer or may be a fitment capable of being attached to a standard,off-the-shelf container.

In respect to the pH changing aspect of this invention, it is noted thata large number of pharmacologically active substances are stable only atpH values which are extreme in the acidic or alkaline region. Thesesubstances cannot be administered at such extreme pH values withoutcausing pain and/or injury to the recipient. This is true whether theadministration is to the eye or another portion of the body of therecipient. However, due to the chemical nature of these substances, theymust be maintained at these extreme pH values for storage stability.Many new drug candidates have been "shelved" as not commercially viabledue to this problem even though their pharmacological activity is good.

The present invention provides a solution to this problem since itpermits the substance to be stored in solution or dispersion at anextreme pH value in the acidic or alkaline range where it is stableuntil the time of its administration. At administration, the solution ordispersion containing the active substance is dispensed through achamber containing the necessary ion exchange material to change the pHto a value which is acceptable to the patient and which will not causepain and/or injury.

Thus, the invention provides a method for the administration of apharmacologically active substance which substance is stable only at apH value which is extreme in the acidic or alkaline region and at whichpH value the substance cannot be administered without causing discomfortand/or injury to a patient, which comprises maintaining the substance ina solution or dispersion at the pH at which the substance is stableuntil the time of administration and administering the substance to thepatient by passing the solution or dispersion containing the substancethrough a chamber containing an ion exchange material which changes thepH of the solution or dispersion to a value which will not causediscomfort and/or injury to the patient.

Therefore, it is an object of the present invention to provide anapparatus which removes preservatives, as well as other components, froma solution as the solution is dispensed to a patient.

It is also an object of the present invention to provide such anapparatus which is easily manufactured and economical to use.

It is also an object of the present invention to provide such anapparatus which may be adapted to a standard solution container.

It is a further object to provide an apparatus and method for storing asolution or dispersion at a given pH value at which a pharmacologicalsubstance contained therein is stable but which is not optimal foradministration and subsequently administering the substance through achamber which changes the pH of the solution or dispersion to a valuewhich is acceptable for administration.

These and other objects and advantages will be more apparent from thefollowing detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an exploded view of a first embodiment of the presentinvention in which scavenging material is provided within a container;

FIG. 2 is a partial cross-sectional view of a first embodiment of thepresent invention in which scavenging material is provided within acontainer;

FIG. 3 is an exploded view of a second embodiment of the presentinvention in which scavenging material is provided within a fitment;

FIG. 4 is a partial cross-sectional view of a second embodiment of thepresent invention in which scavenging material is provided within afitment;

FIG. 5 is a partial cross-sectional view of an embodiment of the presentinvention in which the dispensing head is snap-fitted onto a container;

FIG. 6 is a partial cross-sectional view of an embodiment of the presentinvention having means for providing one-directional flow of solutionout of a container.

FIG. 7 is an exploded view of the present invention in which ionicexchange material is provided within the container;

FIG. 8 is a partial cross-sectional view of the present invention inwhich ionic exchange material is provided within the container;

FIG. 9 is an exploded view of the present invention in which the ionicexchange material is provided in a fitment;

FIG. 10 is a partial cross-sectional view of the present invention inwhich the ionic exchange material is provided in a fitment; and

FIG. 11 is a partial cross-sectional view of the present invention inwhich scavenging material and ionic exchange material are provided inthe container.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the figures, a device 10 for removing components, such aspreservatives, from solutions, such as an ophthalmic solution, is shown.The device 10 includes a container 12, preferably constructed of moldedplastic, having resilient sidewalls 14 which define a solution retainingchamber and which preferably may be deformed by inward pressure toproduce a pressure within the container 12 for using and dispensing itscontents. The container 12 is provided with an upstanding neck portion16 having external threads 18 thereabout. A dispensing head 20 isprovided atop the neck portion 16, either integrally, as shown in FIGS.1-4, by threading engagement, or by snap-fitting engagement as shown inFIGS. 5 and 6. A flange portion 22 is provided between the dispensinghead 20 and the container neck 16. The dispensing head 20 has passagemeans, such as a duct or other passageway, through its length which inturn has a first end in communication with the chamber and a containeroutlet 24 at the other end.

In a first embodiment of the present invention, shown in FIGS. 1 and 2,means for removing preservatives or other components are placed directlywithin the dispenser head 20. In its preferred form, the preservativeremoving means comprise scavenging material 26 provided intermediate thechamber and the container outlet 24, so as to be within the path of thesolution as the solution is dispensed from the container 12. Thematerial 26 should be positioned as close as possible to the outlet 24to minimize empty space in the upper portion of the dispensing head 20.The material 26 may be compressed into a porous mass which is preferablyinsert molded into the dispensing head 20. However, any other means ofmaintaining the material in the path of the solution may also be used.Alternatively, as shown in FIG. 2, the material 26 may be in the form offine particles and held in place by porous supporting members 28 and 30.The members 28 and 30 may be made from porous plastic, such as porouspolyethylene. In either case, it is important that the solution passthrough the scavenging material 26 as it exits the container 12 so thatthe component is removed upon contact with the scavenging material 26.

A second embodiment of the invention, shown in FIGS. 3 and 4, includes afitment 32 having a body 34 which is affixable to a standard-sizecontainer 12, such as described above but without the scavengingmaterial 26 within its dispensing head 20. The lower portion 36 of thefitment 32 is provided with internal threads 38 which complimentarilymate with threads 18 on the outer surface of the neck portion 16 so thatthe fitment 32 may be releasably matable to the container 12. As seen inFIG. 4, when the fitment 32 is in threaded relationship with thecontainer neck portion 16, an internal flange 40 of the fitment 32 restsatop the neck portion 16 to provide a seal between the fitment 32 andcontainer 12. The fitment 32 has a fitment outlet 42 atop a taperedupper section 44, as well as a passage or duct through its length. Thepassage is preferably adjacent to and in flow registration with thecontainer outlet 24 at one end and opens to the fitment outlet 42 at itsother end. In this alternative embodiment, the scavenging material 26 isprovided within the fitment 32, and removes the component, such aspreservative, from the solution as the solution passes from thecontainer outlet 24 to the fitment outlet 42. As in the firstembodiment, the scavenger material 26 may be in solid mass or powder orother form.

FIG. 6 shows a device 10 of the present invention which includes meansfor providing one-directional flow of solution out of the container,such as a check valve 50. Preferably, the valve 50 is a deformable,polymeric valve that is positioned within the container outlet 24 so asto be in flow communication with the interior portion of the dispensinghead 20 at one end and with the atmosphere at a second end. In itsnormal or closed position, the valve 50 does not allow air or solutionto flow into or out of the container 12. However, as a result of thepressure exerted onto the container 12 during use, the valve moves to anopen position that allows the solution to pass through to theatmosphere. When the pressure on the container 12 is stopped, the valve50 closes and any solution remaining atop the valve 50 cannot be pulledback inside the container 12, thereby minimizing the incidence oforganisms reentering the container 12 after use.

Also, when a squeezable container 12 is used, means for drawing air intothe container 12 may be provided for returning the container 12 to itsoriginal shape. Preferably, a second one way check valve 54 is providedwithin the neck portion 16 and below the scavenging material 26. Uponrelease of the container 12 by the user, air is drawn into the container12 by the valve 54, thereby restoring the container 12 to its propershape. Also, because the valve 54 is one-directional, solution fromwithin the container 12 cannot leak out to the atmosphere through thevalve 54. Furthermore, because the second valve 54 is below thescavenging material 26, any organism which should happen to be drawnfrom the air into the container will be deposited into the preservedsolution and killed.

Both the dispensing head 20 of the first embodiment and the fitment 32of the second embodiment may include a closure cap 46. The closure cap46 may have internal threads 48 capable of matingly engaging with eitherthe threads 18 of the neck portion 16, as shown in FIG. 1, or theexternal threads 50 of the fitment 32, as shown in FIG. 3, and restingon flange 22.

Of course, containers other than squeezable plastic types may beutilized. The scavenging material may be placed within an aerosol typedispenser, a solid bottle, or some other container.

Virtually any type of scavenging material 26 for removing a preservativeor other component from solution may be used. For example, removal ofbenzalkonium chloride or other quaternary ammonium compounds can beaccomplished by an ionic exchange mechanism or chemical affinity, forexample, using fumed silica. The scavenging material 26 would preferablybe an inert material with a negative charge, and the positively chargedquaternary ammonium compound would adhere to the material 26 as it flowsthrough the fitment 32 or dispensing head 20, depending on theembodiment. Examples of products capable of removing positively chargedpreservatives such as BAK include AG-50X-8, AG-50X-16, BIO-BS-SM2, andBIO REX70, all available from BIO-RAD Laboratories, Richmond, Calif. andAcropor 5A-6404 available from Gelman Sciences, Ann Arbor, Mich.Similarly, negatively charged components, such as acids, may be removedby using positively charged scavenging material 26. Examples of suchscavenging material includes AG-1, AG-2X8, and AG-10 Alumina fromBIO-RAD Laboratories. For example, it has been found that scavengingmaterial 26 comprising Chelex 100 from BIO-RAD will remove Thimerosalfrom solution. Alternatively, the scavenging material may be porousplastic, such as porous polyethylene, imbedded with a cross-linkedstyrene divinyl benzene which is sulfonated to produce either apositively charged hydrogen form or a negatively charged sodium form.Other scavenging materials useful in the present invention are thoserelating to chemical affinity techniques, such as immunoassay, activesite binding and affinity chromatography.

As one particular example, it has been found that a scavenging materialcomprised of a mixture of "Bio Rex 5" and "AG-4", both BIO-RAD products,in a 75 to 25 ratio will almost completely remove 0.1% sorbic acid froma solution and raise the pH of the solution from 4.0 to 7.0. This isimportant since sorbic acid is a commonly used preservative in contactlens solutions. In addition, sorbic acid is normally stored at pH=7,where it is not stable. At pH=4.0, it is very stable but cannot beinstilled into the eye. The present invention will therefore allowsolution to be stored at low pH and the pH raised to an ocularlyacceptable level as the solution is administered.

Other preservatives that are not directly charged, such aschlorhexadine, could also be removed by the present invention. Forexample, a size exclusion mechanism may be utilized for removing certaintypes of preservative compounds. Overall, the term "scavenging material"as used herein refers to all material which will remove or change thenature of preservatives or other components in a solution exiting thecontainer.

As examples of the ion-exchange resins which can be employed either inconnection with the removal of preservative or pH change aspect of thepresent invention, there may be mentioned those which can safely be usedin the treatment of food under conditions prescribed by the Food andDrug Administration. They are prepared in appropriate physical form andconsist of one or more of the following:

(1) Sulfonated copolymer of styrene and divinylbenzene.

(2) Sulfonated anthracite coal meeting the requirements of ASTM-D388-38,Class I, Group 2.

(3) Sulfite-modified cross-linked phenol-formaldehyde, with modificationresulting in sulfonic acid groups on side chains.

(4) Methacrylic acid-divinylbenzene copolymer.

(5) Cross-linked polystyrene, first chloromethylated then aminated withtrimethylamine, dimethylamine, diethylenetriamine, ordimethylethanolamine.

(6) Diethylenetriamine, triethylenetetramine, or tetraethylenepentaminecross-linked with epichlorohydrin.

(7) Cross-linked phenol-formaldehyde activated with one or both of thefollowing: Triethylene tetramine and tetraethylenepentamine.

(8) Reaction resin of formaldehyde, acetone, and tetraethylenepentamine.

(9) Completely hydrolyzed copolymers of methyl acrylate anddivinylbenzene.

(10) Completely hydrolyzed terpolymers of methyl acrylate,divinylbenzene and acrylonitrile.

(11) Sulfonated terpolymers of styrene, divinylbenzene, andacrylonitrile or methyl acrylate.

(12) Methyl acrylate-divinylbenzene copolymer containing not less than 2percent by weight of divinylbenzene, aminolyzed withdimethylaminopropylamine.

(13) Methyl acrylate-divinylbenzene copolymer containing not less than3.5 percent by weight of divinylbenzene, aminolyzed withdimethylaminopropylamine.

(14) Epichlorohydrin cross-linked with ammonia.

(15) Sulfonated tetrapolymer of styrene, divinylbenzene, acrylonitrile,and methyl acrylate derived from a mixture of monomers containing notmore than a total of 2 percent by weight of acrylonitrile and methylacrylate.

(16) Methyl acrylate-divinylbenzene diethylene glycol divinyl etherterpolymer containing not less than 3.5 percent by weight ofdivinylbenzene and not more than 0.6 percent by weight of diethyleneglycol divinyl ether, aminolyzed with dimethylaminopropylamine.

(17) Styrene-divinylbenzene cross-linked copolymer, firstchloromethylated then aminated with dimethylamine and oxidized withhydrogen peroxide whereby the resin contains not more than 15 percent byweight of vinyl N,N-dimethylbenzylamine-N-oxide and not more than 6.5percent by weight of nitrogen.

These are, of course, illustrative and not exhaustive of those ionexchange resins which can be employed. It is also apparent that theparticular ion exchange resin to be employed will vary with theparticular formulation which is to be passed through it in order toobtain optimal results.

To further illustrate the ion exchange resins for use in the inventionthe following exemplary information is set forth. The following listedresins were obtained from Rohm & Haas Company:

Carboxyl Resins

Amberlite® IRC-76

Modified acrylic polymers in the H⁺ form

Amberlite® IRC-50

Divinylbenzene/methacrylic acid copolymer in the H⁺ form

Dualite® C-433

Sulfonic Resins

Ambersep® 252 H Resin

Sulfonated divinylbenzene/styrene copolymer in the H⁺ form

Amberlite® IR-120(H) -20+40 Resin

Sulfonated divinylbenzen/styrene copolymer in the H⁺ form

Each of the resins was received in the H⁺ form and, in the followingdescribed manner, each was converted to the Na⁺ form. 30 Grams of theresin was placed in a column and 1.5 liters of 4% NaOH was passedthrough the column. Ultra pure H₂ O was then passed through the columnuntil a constant pK_(b) was reached.

    ______________________________________                                        Resin              pk.sub.b                                                   ______________________________________                                        Carboxyl                                                                      Amberlite ® IRC-76                                                                           ˜9.8                                                 Amberlite ® IRC-50                                                                           ˜9.9                                                 Dualite ® C-433                                                                              ˜9.7                                                 Sulfonated                                                                    Ambersep ® 252 ˜9.5                                                 Amberlite ® IR-120                                                                           ˜9.6                                                 ______________________________________                                    

Each of these resins proved to be particularly suitable forincorporation in a device as shown in FIGS. 7 through 10 which iscapable of holding an ophthalmic solution at a first pH and dispensingthe solution at a different pH.

Various pharmacological agents such as drugs, diagnostic agents, ocularlubricants and the like can be administered in accordance with theinvention. As examples, the following can be mentioned:

Antibacterial substances such as beta-lactam antibiotics, such ascefoxitin, ciprofloxacin, n-formamidoylthienamycin and other thienamycinderivatives, tetracyclines, chloramphenicol, neomycin, carbenicillin,colistin, penicillin G, polymyxin B, vancomycin, cefazolin,cephaloridine, chibrorifamycin, gramicidin, bacitracin and sulfonamides:

Aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin,sisomicin and tobramaycin;

Naiidixic acid and its analogs such as norfloxacin and the antimicrobialcombination fluoroalanine/pentizidone, nitrofurazones and analogsthereof;

Antihistaminics and decongestants such as pyrilamine, chlorpheniramine,tetrahydrazoline, antazoline and analogs thereof;

Anti-inflammatories such as diclofenac, ketorolac, cortisone,hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone,dexamethasone sodium phosphate, prednisone, methylprednisolone,medrysone, fluorometholone, prednisolone, prednisolone sodium phosphate,triamcinolone, indomethacin, suiindac, its salts and its correspondingsulfides, and analogs thereof;

Miotics and anticholinergics such as echothiophate, pilocarpine,physostigmine salicylate, diisopropylfluorophosphate, epinephrine,dipivaloylepinephrine, neostigmine, echothiopate iodide, demecariumbromide, carbamoyl choline chloride, methacholine, bethanechol, andanalogs thereof;

Most cell stabilizers such as cromolyn sodium;

Mydriatics such as atropine, homatropine, scopolamine,hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine,cyclopentolate, oxyphenonium, eucatropine, and analogs thereof;

Other drugs used in the treatment of conditions and lesions of the eyessuch as:

Antiglaucoma drugs for example timolol, and especially its maleic saltand R-timolol and a combination of timolol or R-timolol withpilocarpine, as well as many other adrenergic agonists and/orantigonists; epinephrine and an epinephrine complex, or prodrugs such asbitartrate, borate, hydrochloride and dipivefrine derivatives andhyperosmotic agents such as glycerol, mannitol and urea: carbonicanhydrase inhibitors such as acetazolamide, dichlorphenamide,2-(p-hydroxyphenyl)-thio-5-thiophenesulfonamide,6-hydroxy-2-benzothiazolesulfonamide; and6-pivaloyloxy-2-benzothiazolesulfonamide;

Antiparasitic compounds and/or anti-protozoal compounds such asivermectin, pyrimethamine, trisulfapidimidine, clindamycin andcorticosteroid preparations;

Compounds having antiviral activity such as acyclovir,5-iodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A),trifluorothymidine, and interferon and interferon-inducing agents suchas poly I:C;

Antifungal agents such as amphotericin B, nystatin, flucytosine,natamycin and miconazole;

Anesthetic agents such as etidocaine cocaine, benoxinate dibucainehydrochloride, dyclonine hydrochloride, naepaine, phenacainehydrochloride, piperocaine, proparacaine hydrochloride, tetracainehydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine andprilocaine;

Ophthalmic diagnostic agents, such as:

(a) those used to examine the retina such as sodium fluorescein;

(b) those used to examine the conjunctiva, cornea and lacrimalapparatus, such as fluorescein and rose bengal; and

(c) those used to examine abnormal pupillary responses such asmethacholine, cocaine, adrenaline, atropine, hydroxyamphetamine andpilocarpine;

Ophthalmic agents used as adjuncts in surgery, such as alphachymotrypsinand hyaluronidase;

Chelating agents such as ethylenediaminetetraacetic acid (EDTA) anddeferoxamine;

Immunosuppressants and anti-metabolites such as methotrexate,cyclophosphamide, 6-mercaptopurine and azathioprine; and combinations ofthe compounds mentioned above, such as antibiotics/antiinflammatoriescombinations such as the combination of neomycin sulfate anddexamethasone sodium phosphate, and combinations concomitantly treatingglaucoma, for example a combination of timolol maleate and aceclidine.

The foregoing agents will be principally used in the embodiment of theinvention where a preservative agent is removed from a solutioncontaining the agent as the solution is passed through the chambercontaining the "scavenging material". However, in those cases wherethese agents must be stored at an extreme pH--either acidic oralkaline--in order to be stable, they may be administered in accordancewith the pH change aspect of the invention.

Particular examples of drugs which are suitable for administrationaccording to the pH change aspect of the invention are the antibacterialagent tosufloxacin (stable at pH 11), the cholinergic agent pilocarpinehydrochloride (stable at pH 4.5), the antibacterial agent tobramycin(stable at pH 8) and diveprin hydrochloride (stable at pH 2-3).

Referring to FIGS. 7 through 10, a dispensing device 110 which iscapable of holding an ophthalmic solution at a first pH and dispensingthe solution at a different pH is provided. The device 110 includes acontainer 112, preferably constructed of molded plastic, havingresilient walls 114 which define a solution retaining chamber and whichpreferably may be deformed by inward pressure to produce a pressurewithin the container 112 for using and dispensing its contents. Ofcourse, containers other than squeezable plastic types may be used, suchas aerosol type dispensers or solid bottles. The container 112 isprovided with an upstanding neck portion 116 having external threads 118thereabout. A dispensing head 120 is provided atop the neck portion 116,either integrally, by threading engagement or by snapfitting. Thedispensing head 120 has passage means extending through its length, thepassage means having a first end in communication with the chamber and asecond end being the dispensing outlet 126. A cap 122 having threads 124engageable with threads 118 may be provided for closing the container112.

Means for changing the pH of the solution as the solution is dispensedfrom the chamber through the outlet 126 are provided. Preferably the pHchanging means comprise an ionic exchange material 128 provided withinthe path of the solution as the solution travels from the chamber to theoutlet 126. For example, as seen in FIG. 8, the ionic exchange material128 may be located within the passage means of the dispensing head 120.Means for maintaining the ionic exchange material 128 in position withinthe passage means may also be provided. Such position maintaining meansmay be a first supporting member 130 located over the first end of thepassage means and a second supporting member 132 located over the secondend of the passage means. The ionic exchange material 128 will be heldin position between the first and second supporting members 130 and 132,respectively. The supporting members 130 and 132 may be made from porousplastic, such as porous, non-woven polyethylene or polypropylene, orsome other material which is permeable to the solution but which isimpermeable to the ionic exchange material 128.

The type of ionic exchange material 128 used depends upon thecharacteristics of the solution to be dispensed and the desired pHchange. For example, the ionic exchange material 128 is preferably ananionic exchange material capable of removing positively charged ionsfrom the solution when it is desired to raise the pH of the solution asthe solution is dispensed from the chamber through the outlet 126.Alternatively, the ionic exchange material 128 may be a cationicexchange material for removing negatively charged ions from the solutionwhen it is desired to lower the pH of the solution as the solution isdispensed from the chamber through the outlet 126. The ionic exchangematerial 128 may be in the form of a powder, shavings, beads orotherwise so long as the solution can pass through as it is dispensedfrom the container 112. The amount of ionic exchange material 128 useddepends upon a number of factors, including the length and diameter ofthe passage means, the hydrogen ion concentration of the solution, andthe residence time of the solution in contact with the ionic exchangematerial 128. Overall, the length and diameter of the passage means mustbe enough to provide sufficient residence time for the hydrogen ionconcentration of the solution to be changed to the desired final pH.

Another embodiment of the device 110 of the present invention, shown inFIGS. 9 and 10, includes a fitment 134 which is affixable to astandard-size, off-the-shelf container 112, such as described above butwithout the ionic exchange material 128 within its dispensing head 120.The lower portion of the fitment 134 is provided with internal threads136 which complimentarily mate with the threads 118 on the outer surfaceof the neck portion 116 so that the fitment 134 may be releasablymatable to the container 112. As seen in FIG. 10, when the fitment 134is in threaded relationship with the container neck portion 116, a sealis provided between the fitment 134 and the container 112. The fitment134 has a dispensing outlet 138 atop a tapered upper section 140, aswell as a passage or duct through its length. The passage is preferablyadjacent to and in flow registration with the standard container outlet126 at one end and opens to the dispensing outlet 138 at its other end.The ionic exchange material 128, as described above and preferably heldin place by position maintaining means 130 and 132, is provided withinthe fitment 134, and changes the pH of the solution as the solutionpasses from the container outlet 126 to the dispensing outlet 138.

The following example is illustrate of a specific type of device whichcan be made according to the above description, but should not be viewedas limiting any aspect of the invention.

Pilocarpine hydrochloride; chemical name 2(3H)-furanone,3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl]-,monohydrochloride, (3S-cis)-; is a well known direct acting cholinergic(parasympatomimetic) agent causing the pupillary constriction andreduction of intraocular pressure. It is commonly dispensed in abuffered ophthalmic solution which may consist of boric acid, potassiumchloride, hydroxypropyl methylcellulose, sodium, carbonate, EDTA,purified water, and preserved with benzalkonium chloride. A problemexists, however, in that the pilocarpine hydrochloride solution isformulated at a pH of about 4.5 in order for it to remain stable insolution, and such pH is ocularly uncomfortable or otherwiseincompatible. The device 110 of FIGS. 7 and 8 may be used to solve thisproblem by allowing the solution to be maintained at a stabilizing pH ofabout 4.5 while in the retaining chamber of the container 112, yet beingat an ocularly acceptable pH of about 6.5 to 7.0 upon exiting the outlet126.

Since it is desired to raise the pH of the pilocarpine hydrochloridesolution from a relatively low pH of about 4.5 to an ocularly acceptablepH of about 6.8, the ionic exchange material 128 is preferably ananionic exchange material capable of removing positively charged ionsfrom the solution. One such anionic exchange material is Amberlite®IRA-68 (available from Rohm & Haas Company, Philadelphia, Pa. 19105),which is a gel type, weakly basic anion exchange resin possessingtertiary amine functionality in a crosslinked acrylic matrix. Other suchmaterial is BIO-RAD® AG4 and BIO-RAD® AG3, both from BIO-RADLaboratories. The Amberlite® IRA-68 material is available in uniform,spherical particles which can be easily placed within the passage meansof the dispensing head 120 and held in position by porous supportingmembers 130 and 132. It should be noted that because the Amberlite®IRA-68 material attracts acids, it may be necessary to extract the freebases out of the resin material before placing the Amberlite® IRA-68into the dispensing head 120. Failure to do so may result in an unwantedrise in pH of the solution. This can be accomplished by washing theresin in isopropyl alcohol or methanol (i.e., 1 liter of isopropylalcohol for each 100 grams of Amberlite® IRA-68), followed by washingwith sufficient purified water to remove any residual alcohols. Itshould also be noted that the Amberlite® IRA-68 material may swell uponwetting and shrink upon subsequent drying. Therefore, change of thematerial size must be accounted for when filling the dispensing head120. Means for compensating for changes in size of the ionic exchangematerial 128 during the dispensing of the solution may be provided. Forexample, the first supporting member 130 may be constructed of adeformable sponge-like material capable of occupying the space createdduring expansion of the Amberlite® IRA-68 material.

Additionally, it should be clear that the fitment 134, as illustrated inFIGS. 9 and 10, may also be used to change the pH of the pilocarpinehydrochloride. In such an instance, a fitment 134 having Amberlite®IRA-68 material is placed atop a standard, off-the-shelf container ofstabilized, pH 4.5 pilocarpine hydrochloride solution. Upon dispensing,the solution exits outlet 126 and travels through the passage means ofthe fitment 134, where it contacts the Amberlite® IRA-68 material. TheAmberlite® IRA-68 material removes a sufficient number of hydrogen ionsfrom the solution so that the solution has a pH of about 6.8 uponexiting the dispensing outlet 138.

Also, the means for removing a component from the solution as thesolution is dispensed from the chamber through the container outlet, aspreviously described herein, may be combined in the same container orfitment with the means for changing the pH of the solution as thesolution is dispensed from the chamber through the container outlet, asdescribed directly above. In such a device, illustrated in FIG. 11, thescavenging material 26 and the ionic exchange material 128 may both beplaced within the passage means. For example, in the case of the abovedescribed typical pilocarpine hydrochloride solution, the scavengingmaterial 26 would remove the benzalkonium chloride from the solution andthe ionic exchange material 134 would raise the pH from about 4.5 toabout 6.8. The resulting solution would therefore be preservative-freeand ocularly compatible.

From the foregoing description of the invention, it should be seen thatthe present invention provides the ability to dispense preservative-freesolutions from containers housing solutions that are preserved. Whereasthe present invention has been described with respect to specificembodiments thereof, it should be understood that various changes andmodifications will be suggested to one skilled in the art and it isintended that the invention encompass such changes and modificationsthat will fall within the scope of the appended claims.

What is claimed is:
 1. A method for the administration to a patient of apharmacologically active substance which substance is stable only at apH value which is extreme in the acidic or alkaline region and at whichpH value the substance cannot be administered without causing discomfortand/or injury to the patient, which comprises maintaining the substancein a solution or dispersion at the pH at which the substance is stableuntil the time of administration and administering the substance to thepatient by passing the solution or dispersion containing the substancethrough a chamber containing an ion exchange material which changes thepH of the solution or dispersion to a value which will not causediscomfort and/or injury to the patient.
 2. A method according to claim1, wherein the pharmacologically active substance is pilocarpinehydrochloride.
 3. A method according to claim 1, wherein the substanceis present in the form of a solution.
 4. A method according to claim 1wherein the substance is maintained in and administered from a devicefor dispensing an ophthalmic solution, comprising:(a) a container bodydefining a solution retaining chamber therein for retaining a solutionhaving a first pH, said container having an outlet for dispensing thesolution from the chamber; and (b) means for changing the pH of thesolution as the solution is dispensed from the chamber through theoutlet.